Organic compounds

Abstract

The invention relates to compound of the formula (I) in which the substituents are as defined in the specification; in free base form or in acid addition salt form; to its preparation, to its use as medicament and to medicaments comprising it.

1 . A compound of the formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 3  and R 3a  together represent oxo (═O) or 
 R 3  represents hydrogen and R 3a  represents hydroxy or 
 R 3  represents hydrogen and R 3a  represents hydrogen and 
 X represents —C(O)—NR 6 —; —NR 6 —C(O)—, —NR 6 —C(O)—NR 6 —; 
 N represents 0, 1 or 2; 
 m represents 0, 1, 2 or 3; 
 R 1  represents a substituent different from hydrogen; 
 R 2  represents represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclyl group; an optionally substituted alkyl group; 
 R 4  represents hydrogen or a substituent different from hydrogen 
 R 5  represents represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclyl group; an optionally substituted alkyl group; 
 R 6  represents hydrogen, alkyl, cycloalkyl; 
 and provided that R 3a  does not represent hydroxy if n represents 0; 
 and provided that the compounds 
 N-[4-[2-(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-acetamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]-3-fluorophenyl]-acetamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-benzamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-2-methyl-propanamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-3-methyl-butanamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-hexanamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-propanamide; 
 N-[4-[[4,4-bis(4-fluorophenyl)-2,5-dioxo-1-imidazolidinyl]acetyl]phenyl]-propanamide; 
 N-[4-[(2,5-dioxo-4,4-diphenyl-1-imidazolidinyl)acetyl]phenyl]-butanamide; 
 N-[4-[[4,4-bis(4-methoxyphenyl)-2,5-dioxo-1-imidazolidinyl]acetyl]phenyl]-acetamide; 
 N-[4-[[4-ethyl-4-(4-fluorophenyl)-2,5-dioxo-1-imidazolidinyl]acetyl]phenyl]-propanamide; 
 N-[4-[(4-ethyl-2,5-dioxo-4-phenyl-1-imidazolidinyl)acetyl]phenyl]-acetamide; 
 N-[4-[[4-(4-chlorophenyl)-4-ethyl-2,5-dioxo-1-imidazolidinyl]acetyl]phenyl]-propanamide; 
 N-[4-[(4-butyl-2,5-dioxo-4-phenyl-1-imidazolidinyl)acetyl]phenyl]-acetamide; 
 N-[4-[[4-ethyl-4-(4-fluorophenyl)-2,5-dioxo-1-imidazolidinyl]acetyl]phenyl]-3-methyl-butanamide; 
 N-(4-{2-[4,4-bis-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-acetyl}-phenyl)-propionamide; 
 N-{4-[2-(4-benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-phenyl}-isobutyramide; 
 N-{4-[2-(4-benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-3-fluoro-phenyl}-acetamide; 
 N-{4-[2-(4-benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-phenyl}-2,2-dimethyl-propionamide; 
 N-{4-[2-(4-benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-phenyl}-2-methyl-butyramide; 
 N-(4-{2-[4-(3,4-dimethyl-phenyl)-2,5-dioxo-4-phenyl-imidazolidin-1-yl]-acetyl}-phenyl)-propionamide; 
 N-{4-[2-(4-benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-phenyl}-propionamide; 
 4-[4-ethyl-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-ylmethyl]-N-phenyl-benzamide; 
 4-(2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl)-N-phenyl-benzamide; and 
 N-{4-[2-(4-ethyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-acetyl]-phenyl}-propionamide are excluded; 
 in free base form or in acid addition salt form. 
 
   
   
       2 . The compound of formula I according to  claim 1  wherein
 R 1  represents hydrogen, halogen, cyano, nitro, (C 1-8 )alkyl, (C 1-8 )alkyl substituted by halogen, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl, (C 3-8 )cycloalkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkyl, (C 3-8 )cycloalkyl(C 1-8 )alkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkoxy, aryl, aryl(C 1-8 )alkyl, aryloxy, aryloxy(C 1-8 )alkyl, aryl(C 1-8 )alkoxy, aryloxy(C 1-8 )alkoxy, carboxy, carbamyl, hydroxy, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkoxy substituted by halogen, (C 1-8 )alkoxy(C 1-8 )alkyl, (C 1-8 )alkylthio, (C 1-8 )alkylthio(C 1-8 )alkyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfinyl(C 1-8 )alkyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfonyl(C 1-8 )alkyl, amino, (C 1-8 )alkylamino, di(C 1-8 )alkylamino with two identical or different (C 1-8 )alkyl moieties, amino(C 1-8 )alkyl, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl with two identical or different (C 1-8 )alkyl moieties in the di(C 1-8 )alkylamino moiety, amino, (C 1-8 )alkoxy, (C 1-8 )alkylamino (C 1-8 )alkoxy, di(C 1-8 )alkylamino (C 1-8 )alkoxy with two identical or different (C 1-8 )alkyl moieties, aminosulfonyl, (C 1-8 )alkylaminosulfonyl, di(C 1-8 )alkylaminosulfonyl with two identical or different (C 1-8 )alkyl moieties, formyl, (C 1-8 )alkylcarbonyl, formyloxy, (C 1-8 )alkylcarbonyloxy, formyl(C 1-8 )alkyl, (C 1-8 )alkylcarbonyl(C 1-8 )alkyl, formyl(C 1-8 )alkoxy, (C 1 8)alkylcarbonyl(C 1-8 )alkoxy, (C 1-8 )alkoxycarbonyl, (C 1-8 )alkoxycarbonyloxy, (C 1-8 )alkoxycarbonyl(C 1-8 )alkyl and (C 1-8 )alkoxycarbonyl(C 1-8 )alkoxy;   R 2  represents an aryl group or a (C 3 -C 8 )cycloalkyl group or a heterocyclyl group with 3 to 8 ring atoms or a heteroaryl group with 3 to 8 ring atoms or a (C 1 -C 8 )alkyl group;
 wherein said aryl group, (C 3 -C 8 )cycloalkyl group, heteroaryl group, heterocyclyl group group is unsubstituted, mono-substituted, di-substituted or tetra-substituted, the optional substituent(s) being independently selected from the group consisting of halogen, (C 1-8 )alkyl, (C 1-8 )alkyl substituted by halogen, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl, (C 3-8 )cycloalkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkyl, (C 3-8 )cycloalkyl(C 1-8 )alkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkoxy, aryl, aryl(C 1-8 )alkyl, aryloxy, aryloxy(C 1-8 )alkyl, aryl(C 1-8 )alkoxy, aryloxy(C 1-8 )alkoxy, cyano, nitro, carboxy, carbamyl, hydroxy, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkoxy substituted by halogen, (C 1-8 )alkoxy(C 1-8 )alkyl, (C 1-8 )alkylthio, (C 1-8 )alkylthio(C 1-8 )alkyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfinyl(C 1-8 )alkyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfonyl(C 1-8 )alkyl, amino, (C 1-8 )alkylamino, di(C 1-8 )alkylamino with two identical or different (C 1-8 )alkyl moieties, amino(C 1-8 )alkyl, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl with two identical or different (C 1-8 )alkyl moieties in the di(C 1-8 )alkylamino moiety, amino(C 1-8 )alkoxy, (C 1-8 )alkylamino(C 1-8 )alkoxy, di(C 1-8 )alkylamino(C 1-8 )alkoxy with two identical or different (C 1-8 )alkyl moieties, formyl, (C 1-8 )alkylcarbonyl, formyloxy, (C 1-8 )alkylcarbonyloxy, formyl(C 1-8 )alkyl, (C 1-8 )alkylcarbonyl(C 1-8 )alkyl, formyl(C 1-8 )alkoxy, (C 1-8 )alkylcarbonyl(C 1-8 )alkoxy, (C 1-8 )alkoxycarbonyl, (C 1-8 )alkoxycarbonyloxy, (C 1-8 )alkoxycarbonyl(C 1-8 )alkyl, (C 1-8 )alkoxycarbonyl(C 1-8 )alkoxy, —OCH 2 O—, —C(═O)OCH 2 —, —CH 2 OC(═O)— and —CH═CHCH═CH—, the four last-mentioned optional substituents in each case being attached to two adjacent ring carbon atoms of the said moiety and 
 wherein said (C 1-8 )alkyl group is unsubstituted or mono-, di-, tri or tetra-substituted, the optional substituent(s) on the said (C 1-8 )alkyl moiety being independently selected from the group consisting of halogen, cyano, oxo, nitro, amino, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkylthio, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylcarbonyloxy, (C 1-8 )alkoxycarbonyl and (C 1-8 )alkoxy carbonyloxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl, (C 3-8 )cycloalkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkyl, (C 3-8 )cycloalkyl(C 1-8 )alkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkoxy, aryl, aryl(C 1-8 )alkyl, aryloxy, aryloxy(C 1-8 )alkyl, aryl(C 1-8 )alkoxy, aryloxy(C 1-8 )alkoxy, carboxy, carbamyl, hydroxy, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkoxy substituted by halogen, (C 1-8 )alkoxy(C 1-8 )alkyl, (C 1-8 )alkylthio, (C 1-8 )alkylthio(C 1-8 )alkyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfinyl(C 1-8 )alkyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfonyl(C 1-8 )alkyl, (C 1-8 )alkylamino, di(C 1-8 )alkylamino with two identical or different (C 1-8 )alkyl moieties, amino(C 1-8 )alkyl, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl with two identical or different (C 1-8 )alkyl moieties in the di(C 1-8 )alkylamino moiety, amino(C 1-8 )alkoxy, (C 1-8 )alkylamino(C 1-8 )alkoxy, di(C 1-8 )alkylamino(C 1-8 )alkoxy with two identical or different (C 1-8 )alkyl moieties, formyl, (C 1-8 )alkylcarbonyl, formyloxy, (C 1-8 )alkylcarbonyloxy, formyl(C 1-8 )alkyl, (C 1-8 )alkylcarbonyl(C 1-8 )alkyl, formyl(C 1-8 )alkoxy, (C 1-8 )alkylcarbonyl(C 1-8 )alkoxy, (C 1-8 )alkoxycarbonyl, (C 1-8 )alkoxycarbonyloxy, (C 1-8 )alkoxycarbonyl(C 1-8 )alkyl, (C 1-8 )alkoxycarbonyl(C 1-8 )alkoxy; 
   R 4  represents hydrogen, halogen, cyano, nitro, (C 1-8 )alkyl, (C 1-8 )alkyl substituted by halogen, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl, (C 3-8 )cycloalkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkyl, (C 3-8 )cycloalkyl(C 1-8 )alkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkoxy, aryl, aryl(C 1-8 )alkyl, aryloxy, aryloxy(C 1-8 )alkyl, aryl(C 1-8 )alkoxy, aryloxy(C 1-8 )alkoxy, carboxy, carbamyl, hydroxy, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkoxy substituted by halogen, (C 1-8 )alkoxy(C 1-8 )alkyl, (C 1-8 )alkylthio, (C 1-8 )alkylthio(C 1-8 )alkyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfinyl(C 1-8 )alkyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfonyl(C 1-8 )alkyl, amino, (C 1-8 )alkylamino, di(C 1-8 )alkylamino with two identical or different (C 1-8 )alkyl moieties, amino(C 1-8 )alkyl, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl with two identical or different (C 1-8 )alkyl moieties in the di(C 1-8 )alkylamino moiety, amino, (C 1-8 )alkoxy, (C 1-8 )alkylamino (C 1-8 )alkoxy, di(C 1-8 )alkylamino (C 1-8 )alkoxy with two identical or different (C 1-8 )alkyl moieties, aminosulfonyl, (C 1-8 )alkylaminosulfonyl, di(C 1-8 )alkylaminosulfonyl with two identical or different (C 1-8 )alkyl moieties, formyl, (C 1-8 )alkylcarbonyl, formyloxy, (C 1-8 )alkylcarbonyloxy, formyl(C 1-8 )alkyl, (C 1-8 )alkylcarbonyl(C 1-8 )alkyl, formyl(C 1-8 )alkoxy, (C,4)alkylcarbonyl(C 1-8 )alkoxy, (C 1-8 )alkoxycarbonyl, (C 1-8 )alkoxycarbonyloxy, (C 1-8 )alkoxycarbonyl(C 1-8 )alkyl and (C 1-8 )alkoxycarbonyl(C 1-8 )alkoxy;   R 5  represents an aryl group or a (C 3 -C 8 )cycloalkyl group or a heterocyclyl group with 3 to 8 ring atoms or a heteroaryl group with 3 to 8 ring atoms or a (C 1 -C 8 )alkyl group;
 wherein said aryl group, (C 3 -C 8 )cycloalkyl group, heteroaryl group, heterocyclyl group group is unsubstituted, mono-substituted, di-substituted or tetra-substituted, the optional substituent(s) being independently selected from the group consisting of halogen, (C 1-8 )alkyl, (C 1-8 )alkyl substituted by halogen, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl, (C 3-8 )cycloalkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkyl, (C 3-8 )cycloalkyl(C 1-8 )alkoxy, (C 3-8 )cycloalkoxy(C 1-8 )alkoxy, aryl, aryl(C 1-8 )alkyl, aryloxy, aryloxy(C 1-8 )alkyl, aryl(C 1-8 )alkoxy, aryloxy(C 1-8 )alkoxy, cyano, nitro, carboxy, carbamyl, hydroxy, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkoxy substituted by halogen, (C 1-8 )alkoxy(C 1-8 )alkyl, (C 1-8 )alkylthio, (C 1-8 )alkylthio(C 1-8 )alkyl, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfinyl(C 1-8 )alkyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylsulfonyl(C 1-8 )alkyl, amino, (C 1-8 )alkylamino, di(C 1-8 )alkylamino with two identical or different (C 1-8 )alkyl moieties, amino(C 1-8 )alkyl, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl with two identical or different (C 1-8 )alkyl moieties in the di(C 1-8 )alkylamino moiety, amino(C 1-8 )alkoxy, (C 1-8 )alkylamino(C 1-8 )alkoxy, di(C 1-8 )alkylamino(C 1-8 )alkoxy with two identical or different (C 1-8 )alkyl moieties, formyl, (C 1-8 )alkylcarbonyl, formyloxy, (C 1-8 )alkylcarbonyloxy, formyl(C 1-8 )alkyl, (C 1-8 )alkylcarbonyl(C 1-8 )alkyl, formyl(C 1-8 )alkoxy, (C 1-8 )alkylcarbonyl(C 1-8 )alkoxy, (C 1-8 )alkoxycarbonyl, (C 1-8 )alkoxycarbonyloxy, (C 1-8 )alkoxycarbonyl(C 1-8 )alkyl, (C 1-8 )alkoxycarbonyl(C 1-8 )alkoxy, —OCH 2 O—, —C(═O)OCH 2 —, —CH 2 OC(═O)— and —CH═CHCH═CH—, the four last-mentioned optional substituents in each case being attached to two adjacent ring carbon atoms of the said moiety and 
 wherein said (C 1-8 )alkyl group is unsubstituted or mono-, di-, tri or tetra-substituted, the optional substituent(s) on the said (C 1-8 )alkyl moiety being independently selected from the group consisting of halogen, cyano, oxo, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkoxy, (C 1-8 )alkylthio, (C 1-8 )alkylsulfinyl, (C 1-8 )alkylsulfonyl, (C 1-8 )alkylcarbonyloxy, (C 1-8 )alkoxycarbonyl and (C 1-8 )alkoxy carbonyloxy. 
   
   
   
       3 . A process for the preparation of a compound of the formula I as defined in  claim 1 , in free base form or in acid addition salt form, comprising the steps of
 Process A (to obtain a compound of formula (I) wherein X represents —N(H)—C(O)—N(H)—):   reacting of a compound of the formula VI   
     
       
         
         
             
             
         
       
     
     wherein A represents an amino group and the remaining substituents are as defined for the formula (I), with a compound of the formula (VII-A)
   R 5 —NCO   (VII-A) 
 
     wherein R 5  is as defined in formula (I); or
 Process B (to obtain a compound of formula (I) wherein X represents —C(O)—N(H)—): reacting a compound of formula (VI) 
 
     
       
         
         
             
             
         
       
     
     wherein A represents an amino group and the remaining substituents are as defined for the formula (I), with a compound of the formula (VII-B)
   R 5 C(O)-LG   (VII-B) 
 
     wherein R 5  is as defined in formula (I) and LG represents a leaving group, such as a halogen; or
 Process C (to obtain a compound of formula (I) wherein X represents —N(H)—C(O)—): reacting a compound of formula (VI) 
 
     
       
         
         
             
             
         
       
     
     wherein A represents a carboxy group and the remaining substituents are as defined for the formula (I), with a compound of the formula (VII-B)
   R 5 —NH 2    (VII-B) 
 
     wherein R 5  is as defined in formula (I);
 in each case: 
 optionally in the presence of a base, such as a hydride; 
 optionally in the presence of one or more diluents; 
 optionally followed by reduction, oxidation or functionalization reaction of the resulting compound of formula (I) 
 optionally followed by cleavage of protecting groups if present, 
 optionally followed by recovering the so obtainable compound of the formula (I) in free base form or in acid addition salt form. 
 
   
   
       4 . A compound of formula (I′) 
     
       
         
         
             
             
         
       
     
     wherein
 R 3  and R 3a  together represent oxo (═O) or 
 R 3  represents hydrogen and R 3a  represents hydroxy or 
 R 3  represents hydrogen and R 3a  represents hydrogen and 
 X represents —C(O)—NR 6 —: —NR 6 —C(O)—, —NR6-C(O)—NR 6 —; 
 n represents 0, 1 or 2; 
 m represents 0, 1, 2 or 3; 
 R 1  represents hydrogen or a substituent different from hydrogen 
 R 2  represents represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclyl group; an optionally substituted alkyl group; 
 R 4  represents hydrogen or a substituent different from hydrogen 
 R 5  represents represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclyl group; an optionally substituted alkyl group; 
 R 6  represents hydrogen, alkyl, cycloalkyl; 
 and provided that R 3a  does not represent hydroxy if n represents 0; 
 and their pharmaceutically acceptable salts, as medicament. 
 
   
   
       5 - 7 . (canceled) 
   
   
       8 . A method for the treatment, prevention or delay of progression of a condition, disease or disorder, that can be modulated or is mediated by NPY Y2 receptors, comprising:
 administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) as defined in  claim 1  or of the formula (I′) as defined in  claim 4 , in free form or in pharmaceutically acceptable salt form.   
   
   
       9 . A pharmaceutical composition, comprising:
 the compound of the formula (I) as defined in  claim 1 , in free form or in pharmaceutically acceptable salt form, as active ingredient, in association with a pharmaceutical carrier or diluent.   
   
   
       10 . A combination, comprising:
 a therapeutically effective amount of the compound of the formula (I) as defined in  claim 1 , in free form or in pharmaceutically acceptable salt form, and   a second drug substance, for simultaneous or sequential administration.   
   
   
       11 . A pharmaceutical composition, comprising:
 the compound of the formula (I′) as defined in  claim 4 , in free form or in pharmaceutically acceptable salt form, as active ingredient, in association with a pharmaceutical carrier or diluent.   
   
   
       12 . A combination, comprising:
 a therapeutically effective amount of the compound of the formula (I′) as defined in  claim 4 , in free form or in pharmaceutically acceptable salt form, and   a second drug substance, for simultaneous or sequential administration.